B cells are critical players in the orchestration of properly regulated immune responses that provide protection against infectious agents without inflicting auto-inflammatory damage. Achieving this physiological balance requires the finely regulated participation of multiple B cell populations with different antibody dependent and independent functions. This is a rather precarious balance since, as demonstrated by multiple studies, since B cells also mediate powerful pro-inflammatory effector functions which if unchecked contribute to the pathogenesis of multiple pathological conditions of great impact in the health of the population including multiple autoimmune conditions, transplant rejection, atherosclerosis, defective cancer surveillance, COPD, asthma and liver fibrosis. The complexity and clinical relevance of B cells has also been brought to the fore in recent years by the success of Rituximab-based B cell depletion therapy (BCDT) in multiple autoimmune diseases. It is therefore apparent that understanding the phenotypic heterogeneity and functional division of labor among different B cell populations will be critical to unravel the pathophysiology of autoimmune diseases and other major clinical conditions. This central goal will be accomplished through the interactive work of 4 projects and two major cores under the administrative oversight provided by Core A; Project 1: Human transitional B cells: homeostasis, function and impact of BCDT; Project 2: Human effector B cells: homeostasis, function and regulation in SLE; Project 3: Evaluation of IFNg-producing effector B cells in infectious and autoimmune disease; Project 4: Role of B cells in Synovial Inflammation and Lymph Node Remodeling in Inflammatory Arthritis; Core B: Coordinating Clinical Core; and Core C: Biostatistics and Data Management Core. The knowledge derived from the work proposed in this PPG should also enable investigators to better design and evaluate vaccine responses. Finally, and central to this PPG, our results will greatly enhance our ability to design better and safer BCDT therapies and to develop biomarkers of B cell targeted treatments efficacy and safety.